Deck 1 Flashcards
What is often seen with respect to reticulocytes in DHTR in Sickle Cell Disease?
Reticulocytopenia
What are some common RBC antigens that lead to DHTR?
Kidd (Jk) and Rh
What is the goal HbF in someone started on hydroxyurea for SCD?
> 20%
Why are Sickle Cell patients immunocompromised?
Compromised function of the reticuloendothelial system and spleen + autoinfarction of the spleen
What may be used in severe cases of DHTR/Hyperhemolysis in Sickle Cell?
Steroids or IVIG
Though Staph is the MC cause of osteomyelitis, what proportion of osteomyelitis does it account for in Sickle Cell patients?
About 25%—bc mostly Salmonella
What is the most common anti-RBC antibody after ABO and Rh?
Anti-K (Kell)
What antigen on RBCs serves as the receptor for Plasmodium vivax and Plasmodium knowlesi?
Duffy antigen
When doing an exchange transfusion, the recommendation is to keep the Hgb no higher than ____. What is the HbS goal?
No higher than 10 g/dL; <30%
What is the idea behind IVIG (400 mg/kg) x5 days and/or steroids in patients with hyperhemolysis?
IVIG blocks adhesion of sickle cells to MO; steroids suppress MO
What is the normal methemoglobin level in a person with hemoglobin M disease?
15-30%
How would a reticulocyte count help in a person with hemolysis due to B12 deficiency?
It would be low as opposed to elevated in many causes of hemolysis
May also be low in Aplastic Anemia
What blood group antigen does the Parvovirus bind to on RBC precursors when it causes PRCA?
P antigen
What pregnancy category is iron dextran?
C
What iron formulation has a category B designation to administer to pregnant patients?
Iron Sucrose
In patients who develop ACS with SCD, what medication should be given to prevent future episodes?
Hydroxyurea (if not already on)
After a stroke in SCD, what percent of patients will recur without chronic transfusion? What about those getting chronic transfusion?
60% if do nothing; 20% if chronic transfuse to <30% Hgb S; 40% absolute risk reduction
What gene is mutated in Schwachman Diamond?
SBDS—increased cardiotoxicity to cyclophosphamide containing conditioning regimens
Prior to universal vaccination for S pneumoniae how much more likely were children with SCD to get it?
400x
What kind of gel is needed to differentiate HbA2 from HbC?
Citric Agar (they migrate together on normal agar)
HbE migrates with HbA2 on both
What is the normal inheritance pattern for pyruvate kinase deficiency? Gene?
Autosomal Recessive; PKLR
See reticulocytosis >50% after splenectomy
What drug is FDA approved for pyruvate kinase deficiency?
Mitapivat
What happens when a person with SCD and splenic sequestration gets a prbc transfusion? What should be done down the line?
It will regress—after acute episode, need to do splenectomy
In what year was hydrea approved by FDA for Sickle Cell?
1998
2nd MC hemoglobinopathy after homozygous SS disease?
Hb SC dz
What is the MOA of mitapivat?
Pyruvate Kinase Activator
Physiologic function of the Kidd antigen (Jk)?
Urea Transporter
Approximately what percentage of autoimmune hemolytic anemias are Coombs negative?
10%
Usual treatment for warm AIHA?
Steroids generally with rituximab 375 mg/m2 weekly x4
What infections may cause Cold Agglutinin Disease?
Mycoplasma and EBV
What is the most common antigen implicated in pathogenesis of cold agglutinin disease?
I or i
A real cold agglutinin titer should be more than _____
> 1:64
What drug is used in both CAD and WAIHA?
RITUXIMAB.
Rituximab + Prednisone WAIHA; Rituximab + Bendamustine CAD
What treatments often used in WAIHA are not helpful in CAD?
Steroids and splenectomy; upfront WAIHA pred + rituximab—splenectomy later; CAD is rituximab + Bendamustine (unless infectious then tx underlying cause +/- rituximab)
Steroid regimen for WAIHA?
1-2 mg/kg for 3 weeks then slow taper probably with rituximab weekly x4
What is the FDA approved indication for sutimlimab in CAD?
To decrease red cell transfusion needs; can be for sx mgmt in ppl who don’t want Rituximab
What disease has a cold reacting IgG?
Paroxysmal Cold Hemoglobinuria (Donath Landsteiner Hemolysin)
What condition is associated with lack of Kell antigen expression?
McCleod Phenotype —often with acanthocytosis
When would you give ascorbic acid (vitamin C) to a person with methemoglobinemia?
If they have concomitant G6PD def
What is the target of sutimlimab?
Complement C1s (C1s is an activator for the pathway)
Patients with Hereditary Spherocytosis and moderate to severe hemolysis should receive what medication?
Folic acid 1 mg po daily
Hereditary Pyropoikilocytosis is a severe form of what
Hereditary Elliptocytosis
This X-linked disease leads to lack of Kell antigen and acanthocytosis
McLeod Phenotype
Inheritance pattern of G6PD def and Phosphoglycerate Kinase deficiency?
X-linked Recessive
Lead poisoning inhibits this enzyme which can lead to sideroblastic anemia
Pyramidine 5 Nucleotidase
Abbreviation for Kidd antigen? Kell?
Jk—Kidd; K—Kell
In a basic sense—what is thalassemia intermedia?
Nontransfusion dependent thalassemia
What inherited disease presents with normal-high B12 but high MMA and homocysteine and clinical s/s of B12 deficiency?
Transcobalamin II deficiency
What is the most common cause of PRCA in childhood?
Transient Erythroblastopenia of childhood but need to consider Diamond Blackfan Anemia
What is Cooleys anemia?
Beta thalassemia major (absent beta chains: B0/B0)
When to do RBC exchange for babesiosis?
If parasite count is >10%
3 options for FVIII inhibitor bleeding mgmt?
FEIBA, novoseven (rVIIa), and porcine FVIII (obizur)
What can you give Glanzmann refractory to platelets?
Activated Factor VIIa
Recommended VWF level for epidural anesthesia
> 50 iu/dL
MC inherited bleeding disorder?
Von Willebrand Disease—70% is type I
Which type of von willebrand disease does the von willebrand propeptide aid in diagnosis?
Type 1C Vicenza (but now should use DDAVP challenge 1 and 4 hours after)
Reversal agent for Xa inhibitors
Andexanet alfa
Half life of LMWH vs Fondaparinux
4 hr vs 18 hr
Protein S is a cofactor for ____
Protein C
Hereditary deficiency of this clotting factor is associated with poor wound healing and recurrent miscarriages
Factor XIII
Product for factor V deficiency? Goal level?
FFP >20%
What noninferiority study evaluated 20 vs 10 of rivaroxaban in pts who had completed 6 or 12 months AC?
EINSTEIN-CHOICE ok to do 10
VEXAS syndrome involves what gene?
UBA1
In addition to VWF, what clotting factor may become deficient in MPNs and why?
Factor V; due to high platelet/megakaryocyte mass and binding up of the Factor V (alpha granules have factor V)
Test for factor XIII def?
Clot lysis test in 5M Urea
What doac has the least renal excretion?
Apixaban (ie best option for ckd pts)
History of recurrent epistaxis and red telangiectasias on tongue indicate ______
Hereditary Hemorrhagic Telangiectasia
Ie Osler-Weber-Rendu
What genes may be tested for in Osler Weber Rendu?
ACVRL1, SMAD4, and ENG
ie Hereditary Hemorrhagic Telangiectasia
Factor levels for mild, moderate, and severe hemophilia?
> 5-40%, 1-5%, <1%
Diagnostic criteria for any hemophilia involves a respective factor level <____%
40%
For hemophilia patients with severe bleeding factor activity level should be raised to >_____% at all times? Initial?
Should be 50% or more, initially raise to 100%
Which type of hemophilia may be treated with DDAVP?
Hemophilia A (bc FVIII in endothelium)
Perioperative management of a hemophilia pt?
Raise to 100% for surgery; don’t let it fall to <50% until wound healed
If doing prophylactic therapy for hemophilia A (not emacizumab) when should it be started? What is the goal level?
After first bleed; maintain >1%
Difference between plasma and serum?
Serum is plasma minus clotting factors
Do coagulation tests require plasma or serum?
Plasma. Serum does not contain the clotting factors
Which test (PT or aPTT) uses tissue factor? Contact activator?
Tissue factor- PT/INR; Contact Activator- PTT
Normal fibrinogen level?
200-400
What are some factor deficiencies that prolong the PTT that don’t cause bleeding?
XII (Hageman), prekallikrein, contact activation factors
Tissue factor pathway inhibitor (TFPI) blocks what factor?
Factor VIIa
General bleeding profile for factor XI deficiency (hemophilia C)?
Minimal bleeding, if any; may occur after surgery; only AD hemophilia, Askenazi
What are two major clinical considerations for a mixing study that does not correct?
Inhibitor or drug
What does Alice Ma say is the most important enzyme on the planet?
Thrombin
What is the TENET mnemonic for the PTT pathway?
Twelve, Eleven, Nine, Eight, Ten
Reprolongation of a mixing study is seen in which disorder?
Acquired Hemophilia
Lupus inhibitor corrects with the addition of ____
Phospholipids
Brand name of recombinant porcine B domain deleted FVIII?
Obizur
Per the EACH-2 registry what therapy is most likely to eradicate a factor inhibitor in acquired hemophilia?
Prednisone and cyclophosphamide vs pred alone
These are the three antiphospholipid assays
Lupus anticoagulant (DRVVT LA-PTT), anticardiolipin, anti-beta-2-glycoprotein
With respect to the lupus anticoagulant specifically, what are the two assays that can be used?
DRVVT and LA-PTT
What does the platelet count and hematocrit need to be to do a PFA-100?
> 100,000 plt and >30% (hgb > 10)
Acquired von Willebrand disease secondary to MGUS is likely to respond to____
IVIG
What disease may lead to a secondary type I von Willebrand disease?
Hypothyroidism (decreased synthesis with low T4 and T3)
What is seen on the mixing study for factor X def due to amyloidosis?
Correction as it is a true def not inhibitor
Acquired von Willebrand disease secondary to what will respond to IVIG?
Paraproteinemias ie MGUS, myeloma
In the rare situation that a lupus inhibitor is causing bleeding what is probably going on?
Acquired factor II deficiency
A direct thrombin inhibitor is inhibiting which factor by Roman numeral?
IIa as II is PROthrombin; IIa is thrombin
What is the primary clearance of unfractionated heparin?
Liver and RES- ie mainly by macrophages
What are the baseline risks of HIT in patients who are on UFH? LMWH? Risk Ratio?
3%; 0.2%; 15x
Which anticoagulant is primarily cleared by the reticuloendothelial system?
Unfractionated heparin
How is LMWH cleared? Heparin?
LMWH mostly renal; UFH- mostly liver RES
Bone health concern with long term use of LMWH or fondaparinux?
Osteoporosis
Lab monitoring for argatroban and bivalrudin?
aPTT 1.5-3x baseline
In the TRAPS trial how many events were on the rivaroxaban arm in triple positive? Warfarin?
19%, 3%
Renal clearance of rivaroxaban? Apixaban?
Rivaroxaban 66%; Apixaban 27%
DOAC most likely to cause dyspepsia?
Dabigatran due to tartaric acid it is packaged in
In general there is insufficient data for rivaroxaban and apixaban for weight >____ kg and BMI >____ kg/m2
120 kg, 40 kg/m2
What anti platelet drugs are PDE inhibitors?
Dipyridamole and cilostazol
What percentage of patients may develop acute profound thrombocytopenia to GpIIb/IIIa inhibitors
<20k in 0.3%
TTP vs aHUS: comment on the degree of thrombocytopenia, renal impairment, and neurological sx
Plt usually <30 in TTP and > 30 in aHUS; sCr often <2.26 TTP and >2 in aHUS; both may have neuro sx
ADAMTS-13 <____% confirms TTP
<10%
Mortality of untreated and treated TTP?
Untreated 90%, 10-15% with tx
What is the incidence of the full pentad in TTP in the age of plasma exchange?
5%
Ultra large VWF multimers are secreted by ____ normally cleaved by _____
Endothelial cells (Weibel-Palade bodies); ADAMTS-13
Why is there thrombocytopenia in TTP?
Ultra large VWF multimers bind up the platelets then RBC shear across = MAHA
Which anticoagulant is primarily cleared by macrophages of the RES?
Unfractionated heparin
Benefit of adding upfront rituximab to steroids in TTP?
Decreased relapse rate (10% vs 57%) scully blood 2011
What drug is a nanobody targets the A1 domain of VWF and inhibits the VWF-platelet interaction?
Caplacizumab (induces a 2M VWD state)
What are the major benefits of caplacizumab in TTP from the HERCULES trial?
Reduce time to platelet count recovery reduced composite of (TTP related death, recurrent TTP, thrombotic events)
Probable standard of care for TTP (4 things)?
PLEX Steroids, Rituximab, and Caplacizumab
What is the PLEX “dose” for TTP?
1-1.5x plasma volume daily until platelet count normal x2 days
Treatment of choice for TTP in clinical remission but with ADAMTS-13 <10%?
Rituximab 375 mg/m2 weekly x4
What is the idea of the two hit hypothesis for aHUS?
There are genetics for complement proteins that are loss of function for inhibitory complements or gain of function for activating ones; then a trigger like infxn l, surgery, etc
Most common gene mutated in persons at risk for aHUS?
CFH (Factor H) 20-30% of cases
What is the target of eculizumab?
Anti-C5 monoclonal ab
What is the dosing of eculizumab for aHUS?
900 mg weekly x4, 1200 week 5 then 1200 q2weeks
How often is ravulizumab dosed for aHUS?
q8 weeks
What is the relapse rate for aHUS if eculizumab DCd?
20-30% this is analogous to TFR in CML
What proportion of patients with aHUS harbor genetic mutations?
40-60%
What are the two terminal complement inhibitors for PNH/aHUS?
Eculizumab and Ravilizumab (C5 inhibitors)
Pegcetacoplan is C3 (not terminal complement)
Iptacopan is complement factor B
What is a NET with respect to neutrophils?
Neutrophil Extracellular Trap — basically fibers of DNA that are used to trap pathogens but can also trap RBC and plt = microthrombosis
Which histology of malignancy is most likely to cause MAHA?
Adenocarcinoma
What may be the first signs of TMA?
Worsening HTN and AKI
Why might a checkpoint inhibitor cause TTP?
Can trigger autoantibodies to ADAMTS-13 (similar to TA-TMA can get anti-complement factor H)
What is the best mgmt of VEGFi associated TMA?
DC drug + adequate hydration and BP control with ACE/ARB
Tx of TA-TMA and benefit with this therapy in 1 year OS compared to historic controls
Eculizumab; 66% vs 16% (4x increase OS); note narsoplimab also on the rise in this space
Peripheral smear findings for ITP?
Few normal to large platelets; no red or white cell abnormalities
What infections to check in all ITP pts?
HCV and HIV
Activation of FC gamma receptors depends on what molecule ?
Syk (Spleen Tyrosine Kinase); fostamatinib targets
What proportion of ITP is primary? Secondary? MC secondary?
80%, 20%, Lupus accounts for 5% of all, CLL 2%
Average time to response for ITP tx with steroids dex 40 x4?
3-4 days
Time to respond to IVIG for ITP?
24-48 hours
What are the black box warnings for IVIG?
Renal failure and thrombosis
What is the black box warning for WinRho
Fatal Intravascular Hemolysis
Is there a difference using prednisone vs high dose dexamethasone for ITP?
No
Longterm remission rates for relapsed/refractory ITP for 1) Splenectomy 2) Rituximab 3) TPO-RA
Splenectomy 60-70%, Rituximab as low as 20%, TPO-RA work 50% but no durable response after DC
When do you see a response in platelet count in ITP after splenectomy?
7 days
How common is gestational thrombocytopenia? How low does plt go? When?
10% of pregnancy, 70k; 2-3 trimester
MC cause of first trimester thrombocytopenia?
Pregnancy associated ITP
What is the incidence of neonatal thrombocytopenia in pregnancy associated ITP?
20% (1 in 5); 4% severe (1 in 25)
Can you use rituximab in pregnancy associated ITP?
No—contraindicated
Goal plt count for epidural anesthesia
75-100k
In what year was fostamatinib approved for chronic ITP? Dose? ORR?
2018, 100 bid, 43% ORR
Russel Viper Venom directly activates _____
Factor X
What type of pRBC should be used if transfusion needed for an ITP pt on WinRho who needs blood?
Rh (-) so as to not exacerbate ongoing hemolysis
(note: pt needs to have spleen)
What is the extrinsic tenase complex?
Tissue factor + FVIIa (TF:VIIa)
Where is the coagulation cascade occurring?
On the surface of activated platelets
What is the intrinsic tenase complex?
FVIIIa:FIXa
In addition to cleaving fibrinogen to fibrin, thrombin also activates what two other molecules?
FXIII and Thrombin Activatable Fibrinolysis Inhibitor (TAFI)
Both hemophilia A or B will lead to inability to form what complex?
Intrinsic tenase (FVIIIa:FIXa)
The genes for FVIII and FIX are on what chromosome?
X
Incidence of hemophilia A? B?
1:5,000 and 1:30,000 so A is 6x more frequent
What biological phenomenon in women accounts for the wide range of factor levels and clinical manifestations in women with hemophilia?
X inactivation as factors VIII and IX are on X chromosome
This bleeding disorder is most likely to be conflated for Hemophilia A
Type 2N Von Willebrand Disease (but is AR; hemophilia A is X linked recessive)
What was the first treatment for hemophilia (1940)? Then in 1955?
Whole blood (1940); FFP (1955)
The two major paradigmatic types of hemophilia therapy are prophylactic and ______
On-demand
This drug mimics FVIIIs role in the intrinsic tenase complex
Emacizumab by bringing IXa to X
The extended half life hemophilia meds have one of what two chemical modifications?
Pegylation or Protein Fusion (Fc Fusion or Albumin)
What is the long acting Fc-fused FVIII product? Fc-fused FIX product? Albumin fused FIX?
Fc fused VIII = Eloctate
Fc fused IX = Alprolix
Albumin fused IX = Idelvion
What does AAV stand for in gene therapy?
Adeno-associated virus
Explain the dosing for Etranacogene Dezaparvovec as 2x10^13 vg/kg
2 trillion viral/vector genome/ kg
What is used “reactively” in AAV gene therapy?
Steroids to prevent harmful immune response to the AAV capsid (Adenovirus Associated Virus)
For an inhibitor titer greater than 5 BU the term “high responding” is used, what does it mean?
The inhibitor titer rises in response to factor exposure
This is the reciprocal of the dilution that leads to 50% clotting factor in test sample compared to control plasma in hemophilia inhibitors
Bethesda Unit
This experimental drug targets mRNA of antithrombin to try to rebalance hemostasis in hemophilia
Fitusiran (siRNA that prevents mRNA of antithrombin from being translated)
What drug inhibits TFPI (Tissue Factor Pathway Inhibitor)?
Concizumab trying to rebalance hemostasis in hemophilia
What does concizumab do?
Blocks TFPI to rebalance hemostasis in hemophilia (normally TFPI inhibits FVIIa)
MOA of fitusiran
siRNA that prevents formation of antithrombin to try to rebalance hemostasis in hemophilia
In HIT the thrombocytopenia and thrombosis should occur _____ days after the immunizing event
5 days
For rapid onset HIT there usually has been prior heparin exposure within the past ____ days
100
Platelet activating antibodies in HIT often become undetectable within ____ days
100 days
They are transient no immune memory.
So rapid onset really only occurs within 100 days
What is the median platelet nadir in HIT?
55-70k
Difference in median platelet nadir for DITP vs HIT both of which occur 5 days after immunizing event
DITP <10k + bleeding; HIT around 55-70 + thrombosis
The heparin-PF4 complex causes platelet activation by stimulating what receptor?
Platelet Fc-gamma receptor
What is the general spectrum of types of thrombosis that occurs in HIT?
DVT 50%, PE 25%, and arterial 15%; venous:arterial 4:1
Two major tests for HIT?
Serotonin release assay; ELISA for PF4 antibody
What OD level on the PF4 ELISA strongly predicts for a positive SRA in HIT?
> 2
When should you start warfarin for HIT? What if do it too early (2)?
When platelet >150k otherwise can get warfarin skin necrosis or venous limb gangrene
If a person with hemophilia C bleeds at all it is probably in what setting?
After surgery
What two products may be used for factor V deficiency?
FFP and platelets (factor V in alpha granules)
What platelet disorder may have low factor V?
Quebec Platelet Disorder
Effect of lithium on CBC?
Leukocytosis- neutrophilia
Treatment of choice for a child with leukocyte adhesion deficiency
Stem cell transplant
Preferred term for ethnic neutropenia
Duffy-null associated Neutrophil Count (DANC) due to SNPs in DARC
What gene is MC mutated in severe congenital neutropenia?
ELANE (AD)
Chediak Higashi is due to mutations in _____
LYST
If you were to obtain a BMBx on pt with cyclic neutropenia during periods of neutropenia what would you see?
Myelocyte arrest
Primary autoimmune neutropenia is primarily a disease of children, what is the typical clinical course?
Spontaneous remission within 2 years;
Secondary is like with RA in adults
When “HLH” occurs in patients with autoimmune disease, it is referred to as _____
MAS- Macrophage Activation Syndrome
This is the leading trigger of infection associated HLH
EBV
MOA of emapalumab
Inhibits IFN-Y for second line tx of HLH
What maternal blood type has greatest risk of causing hemolytic disease of the newborn?
O+
This type of VWD has selective deficiency of high molecular weight multimers
Type 2A or 2B but 2B has low plt and inc RIPA
This type of von Willebrand disease has increased platelet affinity for platelet Gp1b
Type 2B—now recommended to check DNA analysis over RIPA
This type of von willebrand disease has a very low FVIII level
Type 2N
Which types of von willebrand disease are only inherited autosomal recessive?
Type 2N (FVIII binding site) and Type 3 (absolute deficiency)
What is the prevalence of type 1 von willebrand disease?
1% (1 in 100)
Which blood group had low VWF?
Type O
Where can you find Von Willebrand guidelines?
ASH ISTH NHF WFH 2021 guidelines in Blood Advances
Which types of VWD have preserved ratios of VWF ag, VWF activity, and FVIII?
Type 1 and Type 1C (but higher propeptide); Type 2N has preserved VWF Ag VWF act but super low FVIII
What type of VWD has decreased platelet dependent VWF activity with a preserved multimer pattern?
Type 2M
Which type of VWD is due to a functional defect in platelet GP1b often leading to thrombocytopenia?
Platelet Type VWD
VWF activity:antigen ratio consistent with Type I VWD?
> 0.7
Which VWF Activity:antigen ratio is consistent with a type 2 VWD?
<0.7 with the exception of 2N where the issue is the FVIII binding site
What is now recommended per the 2021 VWD recommendations to dx Type 1C over the propeptide?
DDAVP trial to document clearance
What degree of international units is the target VWF activity level for neuraxial anesthesia?
0.50-1.50 iu/mL (better than >1.5–no need to correct this much)
This multimer pattern is associated with what type of von willebrand disease?
Type IIA Von Willebrand Disease—loss of high molecular weight multimer
(also could be IIB but will have thrombocytopenia)
What is now suggested over RIPA for type 2B Von Willebrand Disease?
Targeted genetic testing (both Type 2B and Platelet Type VWD have abnormal RIPA)
What is the panel recommendation from the 2021 paper for mgmt of VWD pts with hx of severe and frequent bleeds?
Longterm ppx with VWF concentrates (weekly)
In patients with VWD type 1 in need of surgery, what are the goal VWF and FVIII levels?
Both over 50% (0.5 iu/ml)
What are the two basic cutoff levels of VWF to call type I VWD?
<30% or <50% with bleeding
DDAVP should not be used for what types of VWD?
Contraindicated for 2B, generally avoid for types 2 and 3
Iptacopan inhibits what molecule?
Complement factor B
What is Pyrukynd?
Mitapivat (Pyruvate Kinase activator) for pyruvate kinase deficiency
What drug was presented in a LBA at ASH 2022 that is a complement factor B inhibitor that may serve as an oral option for PNH patients with ongoing anemia despite terminal compliment blockade?
Iptacopan
Normal amount of hemoglobin A2 in adults?
2-3.5%
Which hgb is alpha2gamma2?
HbF
Which globin of hgb is located on chromosome 16? 11?
16–alpha; 11– beta
What is the essential difference between thalassemias and hemoglobinopathies?
Thalassemias are quantitative defects in numbers of globin genes; hgbpathies are qualitative defects
Hemoglobin Constant Spring is an example of what type of thalassemia?
Nondeletional Alpha Thalassemia
How many alpha globin alleles are there?
4
Difference between alpha thal silent carrier and alpha thal trait?
Silent carrier = 1 allele deleted; Trait = 2 genes deleted (trans—African; cis—SE Asia)
After how many alpha globin allele deletions do sx become severe?
3 = get HbH—B4 (Cooleys Anemia)
(1 gene del is silent carrier; 2 is alpha thal trait)
Which thalassemia may be acquired in MDS?
Alpha thalassemia
Which thalassemia has HbA2 >3.5% and why?
Beta thalassemia because HbA2 is alpha 2 delta 2 so excess alpha chains are the problem
How many mg of iron are in each unit prbc?
275 mg
MOA of luspatercept?
Ligand trap for TGF-B superfamily ligands (GDF11) to decrease SMAD 2/3 signaling
Which assay is considered to confer the highest risk in APS?
Lupus anticoagulant; either DRVVT or LA-PTT
Initial tx of purpura fulminans and why?
FFP as it contains protein C
List the 5 strong thrombophilias
Antiphospholipid syndrome, Antithombin deficiency, Protein S deficiency, Protein C deficiency, HOMOZYGOUS Factor V
Mgmt of high risk thrombophilia in pregnancy
If no FMHx of clot then post-partum LMWH; if FMHx then antepartum and postpartum
Mgmt of pregnancy associated DVT?
3 month minimum LMWH but MUST contain the 6 week post partum period
Leukocyte Adhesion Deficiency has lack of what marker?
CD18 (an integrin)
Consideration for portal venous thrombosis with bloody diarrhea
Intestinal Infarction
Reasonable choice for FXIII def if no FXIII concentrate around?
Cryoprecipitate
MC transfusion related infection
Hepatitis B
Alloimmune Neonatal Neutropenia assoc with what antigen?
HNA-1a
MC infection in Chediak Higashi? Gene?
S. aureus; LYST
Name one platelet disorder and one coagulation disorder that both have the hallmark of premature lysis of thrombi
Quebec Platelet Disorder; FXIII deficiency
What is one of the classic examples of nondeletional alpha thalassemia?
Hemoglobin Constant Spring
Expected HbS and HbA levels in sickle cell trait?
HbA 60% HbS 40%
Sickle cell anemia results from mutations with which globin gene?
Beta globin
What is the expected ratio of HbS and HbA in a person with sickle-thal?
> 60% HbS, 10-30% HbA (almost the opposite of sickle trait)
TCD velocities >_____ predict for stroke in SCD kids. Mgmt?
200 cm/s; chronic transfusion to HbS <30% x1 yr then hydrea; if already had stroke then keep transfusion going
Which sickling disorders are most likely to have splenic sequestration in ADULTS and why?
Sickle-thal and HbSC as the spleen not autoinfarcted like HbSS
What is the presentation of papillary necrosis in pt with sickle cell?
Hematuria with flank pain or painless hematuria; either of which can be complicated by obstruction
How many times in a person’s life are they likely to get aplastic crisis from parvovirus in chronic hemolytic disorders?
Once; lifelong humoral immunity
Definition by RHC for pulmonary hypertension?
MPAP > 25 mmHg at rest
Maximum tolerated dose of hydrea in SCD is ANC > _____
Should be 1.5 or more
What drug is a hemoglobin S polymerization inhibitor?
Voxelotor —increases hgb 0.5-1.5 g/dL
What drug inhibits P selectin as it’s MOA in SCD?
Crizanlizumab
FDA indication for crizanlizumab
Reduce sickle cell crises in SCD patients > 16 yo
This inhibitor of the fibrinolysis pathway is activated by thrombin and serves to stabilize the clot
TAFI —Thrombin activatable fibrinolysis inhibitor
Hereditary Hemochromatosis type IIa is due to mutations in what gene?
Hemojuvelin (younger age; less arthropathy than HFE)
Name 2 major hepatic concerns with hemochromatosis
Cirrhosis and Hepatocellular Carcinoma
What type of general hemoglobin disorders may lead to polycythemia with elevated EPO?
High affinity hemoglobins
In the absence of comorbidities, iron deficiency should only be considered for ferritin < _____
30 ng/mL
What iron chelators are oral?
Defirasirox and deferiprone
Which iron chelator is IV?
Deferoxamine
Main AE of defirasirox
Renal dysfunction
Main AE of deferiprone
Neutropenia (idiosyncratic)
Main AEs of deferoxamine
Renal and auditory toxicity (route IV/SC)
What monitoring is needed for deferiprone?
Weekly CBC due to idiosyncratic neutropenia
Best mgmt of pt refractory to single agent iron chelation
Dual therapy ie deferoxamine (IV/SQ) + deferiprone
What drug was evaluated in the BELIEVE trial for beta thalassemia?
Luspatercept-aamt
What is the genotype for HbH disease?
(a-/–) ie alpha thalassemia
HbH itself is B4 tetramer
Which alpha thalassemia genotypes require transfusion?
HbH disease (a-/- -) and Hb Barts (- -/ - -) but that mostly leads to death
Most likely cause of thrombocytopenia in a person with HbC disease?
Splenomegaly with sequestration
What 3 drugs in sickle cell disease have been shown to reduce the incidence of painful crises?
Hydroxyurea (1st line), L-glutamine, and Crizanlizumab
Duration of tx for iron deficiency
Oral iron until normalization of Hb, MCV, and MCH then 3-6 months to replete stores
Relative hepcidin concentration in MDS?
Decreased due to impairment of hematopoiesis
What is a congenital type of iron deficiency with failure to respond to iron? Mutation?
IRIDA (Iron Refractory Iron Deficiency Anemia); TMPRSS6
What infectious cause should be investigated as a possible cause of no response to oral iron?
H. pylori
When would you expect a reticulocytosis after beginning iron supplementation?
5-10 days; hgb usually recovers in 2 months
Which IV iron formulation is associated with the highest incidence of hypophosphatemia?
Ferric Carboxymaltose (Injectafer)
Main AE of ferric carboxymaltose (Injectafer)
Hypophosphatemia
Anemia of inflammation leads to sequestration of iron primarily in which cells?
Macrophages
XLSA (X linked Sideroblastic Anemia) leads to what sized cells? Gene mutation?
Microcytic anemia; ALAS2 gene
Hyporeflexia is likely to be caused by what vitamin deficiency with megaloblastic anemia?
B12
PPI will lead to which vitamin deficiency with megaloblastic anemia?
B12
What is the relative M:E ratio in PRCA?
Increased bc low erythroid precursors
What congenital condition should be considered for the DDx of Transient Erythroblastopenia of Childhood (TEC)
Diamond Blackfan Anemia—short stature, thumb issues (RPS19)
What red cell antigen is there positivity for in Diamond Blackfan Anemia?
i
What BM failure condition can be diagnosed with high erythrocyte adenosine deaminase (eADA)?
Diamond Blackfan Anemia (RPS19 and related mutations)
What T cell lymphoma may have autoimmune hemolytic anemia with positive DAT
Angioimmunoblastic T Cell Lymphoma
Diagnostic tests for hereditary spherocytosis?
Osmotic fragility; decreased EMA binding on flow cytometry
Lack of central pallor is code for _____
Spherocytes
Macrocytosis and reticulocytosis >50% after splenectomy are typical findings for which hereditary hemolytic anemia?
Pyruvate Kinase Deficiency (Mitapivat)
What drug is a C1s inhibitor used to decrease transfusions in cold agglutinin disease?
Sutimlimab
What drugs are used for classical PNH?
Eculizumab and Ravulizumab
Deficiency in acute intermittent porphyria?
Porphobilinogen Deaminase
Dx of Acute Intermittent Porphyria?
Elevated urinary porphobilinogen
Diagnosis of what general type of porphyria is made by elevated plasma metal-free protoporphyrins?
Protoporphyrias (EPP —erythropoietic protoporphyria or XLP—X linked protoporphyria)
What are the two protoporphyrias?
Erythropoietic Protoporphyria (EPP) and X linked protoporphyria (XLP)
Diagnosis of a protoporphyria is made by elevation of _______
Elevated plasma metal-free protoporphyrins (>85% in EPP, 50-85% in XLP)
What medications may be associated with porphyria cutanea tarda?
Estrogen
Duffy Null Associated Neutophil Count (DANC) is the preferred nomenclature for _____
Benign Ethnic Neutropenia
aka
Constitutional Neutropenia
This drug is used for erythropoietic protoporphyria (EPP) and X linked protoprphyria (XLP)
Afamelanotide (analogue of alpha-melanocyte stimulating hormone)
Afamelanotide is used for which types of porphyria?
EPP and XLP (protoporphyrias)
Tx of porphyria cutanea tarda?
Phlebotomy + Hydroxychloroquine
Which porphyria can be treated with phlebotomy?
Porphyria Cutanea Tarda (phlebotomy + hydroxychloroquine)
Which porphyria can be treated with hydroxychloroquine?
Porphyria Cutanea Tarda (Tx hydroxychloroquine + phlebotomy)
Which types of porphyria can be treated with givosiran?
Acute Hepatic Porphyrias
Acute Intermittent Porphyria, ALA dehyratase def porphyria, variegate porphyria, and hereditary coproporphria
What RNAi drug can be used for porphyria
Givosiran (for acute hepatic porphyrias)
Sickling disorders with splenic sequestration is defined by spleen enlargement and drop > ____ g/dl from baseline
2 g/dl
DHTR is diagnosed within ____ days of a transfusion. Hyperhemolysis dx how?
Within 21 days; hyperhemolysis has drop “severely” below baseline hb
Mgmt of sickle cell nephropathy
ACEi/ARB
Mgmt of multisystem organ failure from sickle cell?
Exchange Transfusion
Platelets should be > _____ on hydrea for SCD
80k
Assessment of efficacy of hydrea in SCD requires how many months of therapy?
6 months with dose adjustments
What should be obtained for worsening anemia on hydrea in SCD?
Reticulocyte count (should be >80k)
MTD of hydrea should have what ANC, retic, and plt?
ANC> 2k, retic > 80k, and plt > 80k
Persons with hx of vaso-occlusive stroke in SCD should receive what therapy?
Chronic blood transfusions to target HbS <30%
What is the appropriate mgmt of sickle cell pt post partum?
LMWH x6 weeks and if NOT breastfeeding then restart hydroxyurea
These two drugs are good to decrease pain crises in pts on MTD of hydrea in SCD
L-glutamine and Crizanlizumab
ie between 15-35 mg/kg and ANC>2 and plt >80 retic > 80
Within what time frame does voxelotor increase hgb and decrease hemolysis in SCD?
2 weeks
Mutations in _____ are seen in 40% of LGL
STAT5B and STAT3
Why might a pt with celiac have neutropenia
Copper deficiency
What may be seen on BM Bx for copper deficiency
Cytoplasmic vacuoles in myeloid and erythroid precursors
3 MC mutations in CHIP
ASXL1, TET2, and DNMT3A
Flow cytometry using FLAER is for dx of ____. What does FLAER stand for?
PNH; Fluorescein-Labeled Proaerolysin
CD55 and CD59 protect RBCs from what?
Complement mediated destruction
Name some inherited causes of AA (5)
Fanconi Anemia, Dyskeratosis Congenita, Schwachman-Diamond, short telomere syndrome, and Amegakaryocytic thrombocytopenia
Most likely dx for 10 yo boy with short stature, cafe au lait spots and absent radii who develops pancytopenia?
Fanconi anemia (chromosome fragility test)
What heritable BM failure syndrome has pancreatic insufficiency and liver issues
Schwachman-Diamond (SBDS)
What germline mutation has been described in an X linked version of Diamond Blackfan Anemia?
GATA1 usually it is RPS19
Similar pathophysiology to Diamond Blackfan Anemia is seen in which type of MDS?
MDS with 5q del (RPS14 abnormalities)
Tx for Diamond Blackfan?
Steroids and if fail then SCT (mutations in RPS19, RPS24, RPS17)
Which porphyria results from abnormalities in uroporphyrinogen decarboxylase?
Porphyria Cutanea Tarda (UROD)
Tx = phlebotomy and hydroxychloroquine
Abnormality in Porphyria Cutanea Tarda
Uroporphyrinogen decarboxylase deficiency
MOA of Afamelanotide
Analogue of alpha-MSH (melanocyte stimulating hormone) used for EPP and XLP (protoporphyrias)
What causes hypocalcemia in apheresis?
Citrate toxicity
Is hemolysis intravascular or extravascular in acute hemolytic transfusion rxn? DHTR?
Intravascular; extravascular
Is there hemoglobinuria in a DHTR?
Shouldn’t be as it is mostly extravascular hemolysis as opposed to an acute hemolytic transfusion reaction
Expected increment after 1 unit of platelets is _____
30k
Why might a person be hyperkalemic after transfusion? Highest risk in which PRBC preparation?
Due to leakage from RBC; highest in irradiated due to RBC damage
RBC are stored at what temp?
4 C; 39F
MOA of TRALI
Antibodies in donor against HLA or HNA (human neutrophil antigen) in neutrophil in lungs leads to activation of the marginated pool
What is the only HBOC available in the US?
Hemopure available as compassionate use (hemoglobin based oxygen carrier)
Severe thrombocytopenia 1-2 weeks after receiving transfusion? Antibody to what? Tx?
Post transfusion purpura; HPA 1a; high dose IVIG
Preferred AC if needed in esophageal and gastric cancer
LMWH
Effects of OCPs on VWF and protein S?
Increase VWF and decrease protein S
Why is pregnancy high risk for protein S deficiency?
Pregnancy and OCPs decrease protein S already
Type of pRBC and FFP for alloSCT pts who are bidirectional mismatches
O red cell, AB plasma
What severe congenital neutropenia genes are AD? AR? X linked?
AD = ELANE
AR = HAX1
X-linked = WAS (Wiskott Aldrich)
Alloimmune neonatal neutropenia is due to antibodies to which antigen?
HNA-1a
What is deficient in chronic granulomatous disease?
NADPH oxidase
LYST mutations are present in what disease?
Chediak Higashi
What disease can be dx by chromosome fragility to DEB or mitomycin C
Fanconi Anemia
There’s an increased risk of skin cancer In which BMF syndromes?
Fanconi anemia and Dyskeratosis Congenita
What BMF syndrome is treated with androgens (danazol)?
Dyskeratosis Congenita (TERC, TERT, DKC)
Which BMF syndrome is diagnosed with a Flow-FISH?
Dyskeratosis Congenita (TERC, TERT, DKC) ie short telomere syndromes
Job syndrome/Hyper-IgE syndrome has mutations in ____
STAT3 (also seen in LGL)
What is WHIM syndrome? Mutation?
Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (can’t release neuts from BM); CXCR4
Term for inability to release neutrophils from BM
Myelokathexis
Schwachman Diamond syndrome have increased risk of cardiotoxicity to which conditioning agent?
Cyclophosphamide
FDP-AML is due to mutations in ____
RUNX1
What drug inhibits IFN-Y as a second line agent in HLH
Emapalumab
GBA gene is mutated in what disease? Enzyme?
Gauchers; glucocerebrosidase
What PNH drug is a C3 inhibitor?
Pegcetacoplan
MOA of pegcetacoplan
C3 inhibitor in PNH
This cause of BMF is due to biallelic MPL mutations
Congenital Amegakaryocytic Thrombocytopenia (CAMT)
Gray platelet syndrome is due to mutations in _____
NBEAL2
What is the only true way to differentiate type 2B VWD and platelet type VWD?
Genetic testing
What two types of VWD would have increased RIPA? How to differentiate?
Type 2B and platelet type —diff by genetic testing now preferred over RIPA anyway
Wilson disease may cause hemolysis due to deficiency of ____
Hexokinase
What is the target factor X level when repleting?
20%
Inheritance pattern of hemophilia A? Type 2N VWD?
X linked recessive; AR
Mgmt of high risk SVT? Dx?
45 days AC (~6-7 weeks); <5 cm from large vein
Why is there hyperfibrinolysis in Quebec platelet disorder?
Increased urokinase in platelets (and FV def)
What test would differentiate a storage pool vs secretion defect in platelets?
Electron Microscopy
What are the macrothrombocytopenias?
MYH9 related, gray platelet (NBEAL2) Bernard Soulier (GP1b/IX) and Montreal Platelet Syndrome
MYH9, Sebastian, Fechtner, and Epstein syndromes make up this eponymous abnormality
May-Hegellan
Tx of congenital TTP (Upshaw Schulman syndrome)
FFP to replace ADAMTS13
What is abnormal in EPP?
Ferrochelatase
Abnormalities in ferrochelatase are seen in which porphyria?
EPP
MOA of givosiran
siRNA that breaks down ALAS1 mRNA and reduces ALAS1 mRNA in hepatic porphyrias
This term refers to failure of neutrophils to leave the BM
Myelokathexis (MC in WHIM syndrome with CXCR4 mutations)
In what proportion of renal transplantation may post transplant polycythemia develop?
10-15% mc in men; tx = ACE/ARB
Classic lab finding after splenectomy for pyruvate kinase deficiency
Reticulocytosis > 50%
Porphobilinogen deaminase is deficient in which porphyria?
Acute intermittent porphyria; givosiran can be used to prevent attacks; on the trial it was almost all AIP (93-96% on each arm)
